Targeting deregulated AMPK/mTORC1 pathways improves muscle function in myotonic dystrophy type I

Marielle Brockhoff, Nathalie Rion, Kathrin Chojnowska, Tatiana Wiktorowicz, Christopher Eickhorst, Beat Erne, Stephan Frank, Corrado Angelini, Denis Furling, Markus A Rüegg, Michael Sinnreich, Perrine Castets

Research output: Contribution to journalArticlepeer-review


Myotonic dystrophy type I (DM1) is a disabling multisystemic disease that predominantly affects skeletal muscle. It is caused by expanded CTG repeats in the 3'-UTR of the dystrophia myotonica protein kinase (DMPK) gene. RNA hairpins formed by elongated DMPK transcripts sequester RNA-binding proteins, leading to mis-splicing of numerous pre-mRNAs. Here, we have investigated whether DM1-associated muscle pathology is related to deregulation of central metabolic pathways, which may identify potential therapeutic targets for the disease. In a well-characterized mouse model for DM1 (HSALR mice), activation of AMPK signaling in muscle was impaired under starved conditions, while mTORC1 signaling remained active. In parallel, autophagic flux was perturbed in HSALR muscle and in cultured human DM1 myotubes. Pharmacological approaches targeting AMPK/mTORC1 signaling greatly ameliorated muscle function in HSALR mice. AICAR, an AMPK activator, led to a strong reduction of myotonia, which was accompanied by partial correction of misregulated alternative splicing. Rapamycin, an mTORC1 inhibitor, improved muscle relaxation and increased muscle force in HSALR mice without affecting splicing. These findings highlight the involvement of AMPK/mTORC1 deregulation in DM1 muscle pathophysiology and may open potential avenues for the treatment of this disease.

Original languageEnglish
Pages (from-to)549-563
Number of pages15
JournalJournal of Clinical Investigation
Issue number2
Publication statusPublished - Feb 1 2017


  • AMP-Activated Protein Kinases/genetics
  • Adult
  • Aminoimidazole Carboxamide/analogs & derivatives
  • Animals
  • Disease Models, Animal
  • Female
  • Humans
  • Male
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Mice, Mutant Strains
  • Middle Aged
  • Multiprotein Complexes/antagonists & inhibitors
  • Muscle Fibers, Skeletal/enzymology
  • Muscle Relaxation/drug effects
  • Myotonic Dystrophy/drug therapy
  • Myotonin-Protein Kinase/genetics
  • Ribonucleotides/pharmacology
  • Signal Transduction/drug effects
  • Sirolimus/pharmacokinetics
  • TOR Serine-Threonine Kinases/antagonists & inhibitors


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